In this study, we present evidence that ER stress and hypercholesterolemia in mice induces the phosphorylation of macrophage FMRP on S500 by the inositol‐requiring enzyme‐1 (IRE1), a conserved endoplasmic reticulum (ER) stress‐sensing kinase/endoribonuclease (RNase). The gene discussed is ERN1; the disease is familial hypercholesterolemia.